Aggregation of the amyloid beta (Aβ) protein into fibrillar plaques is one of main pathological features of Alzheimer’s disease (AD). However, the exact role of amyloid plaques in AD and onset of dementia is unclear. Aβ aggregation in-vitro has been studied extensively, and it is known that mature Aβ fibrils have a primarily parallel beta sheet structure, while early-stage aggregates can exhibit other secondary structures. However, it is yet to be fully understood to what degree these in-vitro structural determinations translate to amyloid structures in different plaques in AD brain tissues. Investigating structural ensembles of different amyloid aggregates in tissues is experimentally challenging, as current approaches for in-vitro structure determination cannot spatially resolve spectra. Without spatial resolution, it is difficult to unequivocally attribute spectral features to specific aggregates or plaque morphologies. Infrared (IR) confocal imaging, which integrates microscopy with IR spectroscopy, is a technique uniquely suited to circumvent this challenge and provides the best of both worlds: spatial resolution and structural sensitivity.<br/>We have used IR confocal imaging to identify the spectral signatures of amyloid plaques in ex-vivo tissue specimens, and our results unequivocally demonstrate that amyloid plaques from the same tissue specimen and of similar morphology exhibit significant heterogeneities in terms of their secondary structure and phospholipid content. IR imaging also identified numerous non-plaque beta sheet deposits distributed throughout the tissues that appear to be more abundant in diseased specimens. Our work underscores the capabilities of discrete frequency IR imaging (DFIR) for rapid, label-free characterization of amyloid deposits in brain. Using DFIR, we have further identified the presence of antiparallel beta sheet structures in certain cored plaques and glial cells. We complement these results using nanoscale spectral data from individual aggregates. AFM-IR is a technique that integrates IR spectroscopy with an atomic force microscope (AFM-IR) and offers the unique capability of acquiring IR spectra that are sensitive to protein structure with nanoscale resolution, so characteristic features of individual aggregates and fibrils can be measured. Insights from AFM-IR spectra of fibrils and prefibrillar aggregates and how they add to our understanding the plaque heterogeneities in AD tissues will be discussed.

Multiscale infrared spectroscopic imaging of amyloid aggregates in Alzheimer’s disease tissues

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ACS Fall 2022

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